The present invention relates to imidazolidine compounds that can affect the activity of the androgen receptor (AR). In one aspect a compound of the invention is an antagonist or partial antagonist and is of use in the prevention and/or treatment of androgen dependent tumors and/or all the conditions in which AR stimulation could be detrimental such as acne, alopecia and/or hirsutism; or in an alternative aspect a compound of the invention is a selective androgen receptor modulator (agonist or mixed agonists/antagonist) that can be used in the treatment of conditions of cachexia and muscle wasting disorders (including but not limited to cancer-induced cachexia, HIV-induced, glucocorticoid-induced, immobilization-induced, diet-induced muscle loss, thermal burns, chronic renal failure, congestive heart failure, chronic obstructive pulmonary disease) age-related functional decline (including but not limited to sarcopenia) and/or male or female osteoporosis. The present invention also provides processes for the production of compounds of the invention, pharmaceutical compositions containing a compound of the invention and the use of a compound of the invention in the prevention or treatment of the disorders disclosed herein.
In men, androgens, of which testosterone and its metabolite 5α-DHT are the main endogenous representatives, are associated with the development and maintenance of the primary male characteristics (epididymis, vas deferens, prostate, external genitalia) and secondary male characteristics (development of hair, musculature of the larynx, distribution of fatty tissue, behaviour and libido). In addition, they contribute to muscle and bone development, and also act on the hematopoiesis, the central nervous system and sexual function.
In women, androgens have been involved inter alia in the development and maintenance of bone tissue and libido.
Progressive reduction in levels of circulating androgens in aging men (PADAM—partial androgen decline in aging men) contributes to a specific number of clinical manifestations, including osteoporosis, loss of muscle mass and strength, reduction in libido and sexual dysfunction, anemia and a change in cognition, mood swings, depression (see Review in: Kaufman J M and Vermeulen A., 2005, The decline of androgen levels in elderly men and its clinical and therapeutic implications Endocr Rev. 26:833-76). However, the clinical safety of androgen therapy for cardiovascular and prostate diseases is uncertain. Therefore, androgen supplementation is not recommended for healthy, elderly men (Liu P Y et al. 2004, Clinical review, 171: The rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations. J. Clin. Endocrinol. Metab. 89:4789-96).
A syndrome associated with the reduction in levels of circulating androgens (ADIF—androgen decline in female) has also been described in women. It can have various causes, including aging, chemotherapy and infection by the AIDS virus. Associated symptoms include: osteoporosis/osteopenia, sarcopenia and muscle weakness, reduction in libido, sexual dysfunction, change of cognition, mood swings, and depression. Endometriosis and an increased risk of breast, uterine and ovarian cancers have also been described (Davison S L and Davis S R 2003 Androgens in women. J. Steroid Biochem. Mol. Biol. 85:363-366). The administration of high doses of androgens to women can lead to the appearance of signs of masculinisation, mood swings and acne. These risks must be taken into consideration when administering androgens to women.
The limitations to the use of steroidal androgen receptors agonists or antagonists, becomes clear as these are plagued with undesirable effects due to their metabolisation into other sex-hormones and steroids, which in-turn induce undesirable effects.
Therefore, non-steroidal alternatives are being investigated and are particularly desired because they allow the beneficial effects of testosterone on specific organs (bone and muscle tissue) and on the libido to be maintained, and are less likely to lead to secondary effects in specific tissues, such as the prostate in men and the uterus in women, as they would not interfere with the hormonal system. They represent a safer alternative to conventional therapies in any pathologies linked with an androgen deficit, including osteoporosis or sarcopenia, and decline in libido associated with syndromes of the PADAM and ADIF type. They may also be used in the treatment of cachexia induced by specific diseases, such as cancer or AIDS, or in the treatment of muscle loss induced by long-term treatment with glucocorticoids. Moreover, they may be used in the treatment of androgen dependent tumors, such as prostate cancer, or hyperplasia, which growth at an early stage can usually be regulated by administering steroidal anti-androgens.
Selective modulators of the androgen receptor (SARMs—selective androgen receptor modulators) of non-steroidal structure are molecules which act as ligands of the androgen receptor (AR) with a degree of tissue specificity.
The importance of the AR as a target is great in many areas of drug discovery and therapy. The compounds of the invention disclosed herein are suggested to have two main modes of action:                As antagonists (complete or partial), inhibitors of the AR may be employed in oncology, and may be particularly useful in the treatment of androgen dependent prostate cancer. They may also be used for male contraception and benign hyperplasia of the prostate, ovarian and breast cancer (for a comparative review, see Mohler et al., Expert Opin. Ther. Patents (2005) 15(11), 1565-1585).        As agonists (complete or partial, including mixed agonists/antagonists), they may be particularly useful for metabolic and endocrine diseases disorders, especially age-related diseases and conditions of cachexia. Additionally due to their presence in bone-cells, SARMs advantageously may be used in the development and maintenance of the skeleton.        
Unfortunately currently available androgens are still flawed with side effects, (such as gynecomastia or breast tenderness), due to low tissue selectivity and potent SARMs with fewer side effects are highly desirable.
EP-A-0966447 discloses a number of imidazolidine compounds useful in the treatment of inflammatory and immune cell-mediated conditions, and which act by inhibiting the interaction of cellular adhesion molecules. Although the compounds disclosed therein are similar to those of the present invention, in some respects, there is no disclosure of any compounds falling within the scope of the present invention.
EP-A-0572191 discloses certain imidazolidines substituted with an iodopropargyl group, useful as antimicrobial agents.
WO 2007/137874 discloses imidazolidine compounds similar to those of the present invention but wherein, in Formula (I), at least one of R3a or R3b is OH, SH or a derivative thereof. These compounds require an OH or SH group to be available in the active compounds in order to be able to bind His-874 of the androgen receptor. These compounds show high in vitro activity but disappointingly low in vivo activity, such that these compounds are not deemed commercially viable.
Surprisingly, it has now been found that in vivo activity can be substantially increased by eliminating the weakly acidic phenolic OH or SH group, or derivatives that can yield this OH or SH, from the R3 position.